1347
We acknowledge the contribution of Bristol-Myers Squibb to the costs of organising the trial.
Endobulln treatment - -I-
MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology,
No Immunoglobulin Infusion
Royal Brompton National Heart and Lung Hospital, London SW3 6NP, UK
JANET H. DARBYSHIRE
JEAN-PIERRE ABOULKER, behalf of the MRC/ANRS International Coordinating Committee for the European/ Australian Alpha Trial
on
Unité de Recherches Statistiques,
INSERM Villejuif, France
1. Khan JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581-87.
A1 B8DR3-associated
expansion in HIV infection SiR.—Dr Oksenhendler and colleagues (July 25, p 207) report 3 HIV-infected white patients characterised by pseudotumoural splenomegaly, polyclonal CD8-positive T-cell expansion, and sharing of the extended A1B8DR3 major histocompatibility complex haplotype. We report a similar case showing that T-cell expansion may not be restricted to lymphoid tissue. A 40-year-old Gambian man was referred to our institution because of acute renal failure (creatinine 1435 pmol/1) in the setting of nephrotic syndrome. He had major splenomegaly and hepatomegaly, peripheral lymphadenopathy, and parotid enlargement. A renal biopsy disclosed focal and segmental glomerulosclerosis and striking interstitial infiltration by numerous CD8-positive, CD25-negative, HLA class II-positive T cells. At the same time, the patient proved HIV-1positive by enzyme-linked immunosorbent assay and western blot. Serological tests for HIV-2, HTLV-1, and HTLV-2 were negative. No opportunistic infection was found. CD4-positive and CD8-positive T-cell counts were 228/ul and 1292/ul, respectively. Salivary gland biopsy showed a lymphocytic infiltrate compatible with a diagnosis of Sjogren’s syndrome. HLA typing was A1B8DR3. Treatment by zidovudine and methylprednisolone resulted in sustained improvement in renal function (creatinine 376 umot/1), and haemodialysis was stopped for 10 months. This report shows that the A1B8DR3-linked CD8-positive T-cell expansion described by Oksenhendler et al in HIV-1infected patients may not arise only in the spleen and that it can involve organs outside the lymphoid system. We suggest that this expansion might account for some visceral complications of HIV infection, such as interstitial nephritis. It may, in some cases, be amenable to antiretroviral and corticosteroid treatment. Service of Clinical Immunology, INSERM U25, and Laboratory of Anatomy and Renal
Pathology,
Hôpital Necker, 75743 Paris, France
Survival of AIDS patients after IVIG therapy.
CD8-positive T-cell
groups of patients were similar in age, weight, low number of CD4 cells, treatment, previous infections, and time between AIDS and entry to the study. All patients had been receiving antiretroviral therapy for 3 months or more at the beginning of study. Clinical evaluation was every month before every IVIG administration.
Laboratory tests (serum immunoglobulins, complement fractions, &bgr;2-microglobulin, transaminases, T-cell counts [CD2, CD3, CD4, or CD8 phenotype], and B-cell counts [CD19, CD20, or CD21 phenotype]) were done every 3 months. IVIG infusions were well tolerated in all patients. No high temperatures, headache, or nausea were observed and no modification of the infusion schedule was necessary in any patient at any time. Survival was significantly better in the IVIG-treated group than in the controls (figure, p < 0-01). 50% of IVIG patients survived 450 days, while less than 50% reached a 200-day survival among controls. After 12 months of follow-up, 9 patients in the IVIG group were alive compared with 3 controls. In addition, and as a possible explanation, the episodes of serious and moderate bacterial or viral infections were fewer in the IVIG-treated group. This study establishes that IVIG has some clinical benefit in adult patients with AIDS. The mechanism of this benefit and the selection of the most appropriate patients deserve further
investigations. Transplantation and Clinical Immunology Unit, Pavillion P, Hôpital Edouard Herriot, 69437 Lyon, France
T. SAINT-MARC J-L. TOURAINE
N. BERRA
1. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency disease. N Engl J Med 1991; 325: 110-17. 2. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 325: 73-80.
JEAN-PAUL VIARD LAURE-HÉLÈNE NOËL DOMINIQUE DROZ JEAN-FRANÇOIS BACH
Beneficial effects of intravenous immunoglobulins in AIDS SiR,—With the introduction of intravenous formulations, the use of immunoglobulins, once limited to IgG replacement in severe humoral immunodeficiencies, has been extended to include the prevention or treatment of infections and immunological disorders.1 Controlled studies in children with HIV infection have shown that immunoglobulin reduces the frequency of bacterial infection and morbidity without changing mortality? We have evaluated the clinical and immunological effects of systematic and regular infusions of immunoglobulins in adults with severe deficiency of cell-mediated immunity and of antibody production because of HIV infection. Between January, 1990, and October, 1991, 24 AIDS patients were enrolled in a prospective trial. All patients were randomised to receive either no additional treatment (controls) or a monthly infusion of intravenous immunoglobulin (IVIG) (Endobulin, lmmunoFrance) at 200 mg/kg for at least 12 months. The two
Role of glucose and insulin resistance in development of type 2 diabetes mellitus SIR,-Dr Martin and colleagues’ study (Oct 17, p 925) of the predictive power of measures of insulin resistance (SD and insulin-independent glucose elimination (Sg) in the development of non-insulin dependent diabetes mellitus (NIDDM) is to be welcomed. This large prospective study of the offspring of parents with NIDDM in 6-25 years of follow-up predicted some 75% of cases of diabetes in subjects with the lowest quintiles of both S; and Sg, who had normal glycaemia at the outset of the study, and for at least 10 years before the onset of NIDDM. By contrast, no offspring in the highest quintile of Sj and Sg developed diabetes in this time. The technique used by Martin et al was the standard intravenous glucose tolerance test (IVGTT) with analysis by the minimum model teclmique.1 A feature of Martin’s study was the use of a higher dose of glucose (05g/kg) than that used by Bergman et aU This will have had the effect of increasing the endogenous insulin response, thus improving the success rate of the subsequent modelling.2 Martin et al successfully analysed 97% of cases. Our experience with this technique has been similar,3-S with an average 96%
success rate.
1348
Minimum modelling of the IVGTT uses a complex analytical technique but the clinical procedure is straightforward and applicable to large groups, unlike the reference standard method for measuring insulin resistance, the euglycaemic clamp. In addition the minimum model provides other important infonnation-for example, the glucose-dependent glucose disappearance rate, Sg, which, according to Martin et al, has almost as good predictive power as measurement of Sj for development of NIDDM. A further refinement of the minimum model technique enables derivation of terms for first and second phase insulin delivery, 01 and 02’ It must be emphasised, however, that these are misleadingly referred to as pancreatic insulin secretion measures by Martin et al. Rather, 0l and 0 refer to insulin delivery into the general circulation, after a large and probably variable proportion of newly secreted insulin has been extracted by the liver.6 Hepatic insulin extraction is reduced in obesity and most of those who developed diabetes in Martin’s study were obese. There may, therefore, have been an impaired pancreatic response to glucose in these subjects, which was disguised by reduced hepatic insulin extraction. The simultaneous measurement of plasma C-peptide (not available when Martin et al’s study was begun) would enable this uncertainty to
be resolved.7
Finally, Martin et al show that predictions of the future development of NIDDM may become possible, especially for vulnerable groups, and in this respect the technique may play a part in diabetes prevention, similar to that of measurement of serum cholesterol and lipoproteins in the prediction of coronary heart disease.
Wynn Institute for Metabolic Research, London NW8 9SQ, UK
IAN F. GODSLAND CHRISTOPHER WALTON VICTOR WYNN
Bergman R, Ider Y, Bowden C, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667-77. 2. Yang Y, Youn J, Bergman R. Modified protocols improve insulin sensitivity estimation using the minimal model. Am J Physiol 1987; 253: E595-602. 3. Bruce R, Godsland I, Stevenson J, et al. Danazol induces resistance to both insulin and glucagon in young women. Chn Sci 1992; 82: 211-17. 4. Walton C, Godsland I, Proudler A, Felton C, Wynn V. Evaluation of four mathematical models of glucose and insulin dynamics with analysis of the effects of age and obesity. Am J Physiol 1992; 262: E755-62. 5. Godsland I, Crook D, Walton C, Wynn V, Oliver M. Influence of insulin resistance, secretion, and clearance on serum cholesterol, triclycerides, lipoprotein cholesterol, and blood pressure in healthy men. Arterioscler Thromb 1992; 12: 1030-35. 6. Horwitz D, Starr J, Mako M, Blackard W, Rubenstein A. Proinsulin, insulin and C-peptide concentrations in human portal and peripheral blood. J Clin Invest 1975; 1.
55: 1278-83. 7. Watanabe R, Vølund A, Roy S, Bergman R. Prehepatic beta-cell secretion during the intravenous glucose tolerance test in humans: application of a combined model of insulin and C-peptide kinetics. J Clin Endocrinol Metab 1989; 69: 790-97.
SIR,-Dr Martin and colleagues report data suggesting defects in insulin sensitivity and non-insulin-mediated glucose disposal as the primary determinants of type 2 (non-insulin dependent) diabetes. Whereas reduced insulin sensitivity has clearly an important role in the pathophysiology of type 2 diabetes, we feel that the data presented do not necessarily prove that it is insulin insensitivity rather than beta-cell dysfunction that is the primary abnormality. Type 2 diabetes is a heterogenous disease and the primary defect varies according to the population studied. Thus, these findings in offspring of diabetic parents may not be generally applicable to all those with type 2 disease. Although insulin insensitivity seems important in certain populations,! in other subsets a genetically determined defect in beta-cell function is the primary defect.2 Even in individuals with reduced insulin sensitivity, beta-cell deficiency is a prerequisite for the development of diabetes. In this respect, it is noteworthy that subjects with some of the distinct syndromes characterised by severe insulin resistance due to inherited disorders of the insulin receptors frequently do not have diabetes, provided that they have adequate beta-cell function.4,5 The methods used in Martin’s study were clearly not designed to detect subtle early defects in insulin secretion but it is notable that in the few subjects studied several times a reduction in beta-cell function preceded the development of diabetes. Furthermore, an increase in the proportion of proinsulin is one of the features of type 2 diabetes.6 The assay for insulin used by investigators would be
expected to cross-react with proinsulin and thus underestimate insulin sensitivity in those individuals with beta-cell dysfunction characterised by increased secretion of proinsulin-like molecules. The measurement of biologically active insulin in these individuals with the new specific insulin assay7 may well reveal evidence of beta-cell deficiencv rather than increased beta-cell function. Department of Medicine, Manchester Royal Infirmary, Manchester M13 9WL, UK
SUDHESH KUMAR ANDREW BOULTON
Doncaster Royal Infirmary, Doncaster
JOHN HOSKER
1. Knowler WC, Pettit DJ, Saad MF, Bennett PH. Diabetes mellitus in the Pima Indians: incidence, risk factors, and pathogenesis. Diabetes Metab Rev 1990; 6: 1-27. 2. Hattersley AT, Turner RC, Permutt MA, et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 1992; 339: 1307-10. 3. Turner RC, Holman RR. Insulin rather than glucose homoeostasis in the pathophysiology of diabetes. Lancet 1976; i: 1272-74. 4. Moller DA, Flier JS Insulin resistance: mechanisms, syndromes, and implications. N Engl J Med 1991; 325: 938-48. 5. Flier JS, Young JB, Landberg L. Familial insulin resistance with acanthosis nigricans, acral hypertrophy, and muscle cramps. N Engl J Med 1984; 303: 970-73. 6. Porte D Jr, Kahn SE. Hyperproinsulinaemia and amyloid in NIDDM. Diabetes 1989; 38: 1333-36. 7. Sobey WJ, Beer SF, Carrington CA, et al. Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65-66 and 32-33 split proinsulins. Biochem J 1989; 260: 535-41.
Cardiotocography and doppler velocimetry for surveillance of small-for-gestational-age
fetuses SIR,-Dr Almstrom and colleagues (Oct 17, p 936) evaluate a technique that shows great promise. However, before their recommendations can be implemented, their study needs closer scrutiny, clarification, and comment. They claim that their two groups are matched in everything apart from smoking, which, as they rightly point out, is associated with poorer outcome. In fact the doppler group has the higher proportion of smokers and yet there were significantly more operative interventions for fetal distress in the cardiotocography (CTG) group. This finding implies either that doppler velocimetry has some therapeutic effect in the prevention of fetal hypoxia and intrapartum fetal distress or, more likely, that the groups were not as new
matched as
is led to believe. Indeed they go on to say that the had doppler group "significantly more operations due to breech presentations and fetopelvic disproportion" whereas the CTG group had significantly more adverse factors such as pre-eclampsia and oligohydramnios. I believe that the groups are not comparable, which might account for the differences in the incidence of fetal distress. Furthermore, to suppose that many of these significant differences were due to chance is contrary to statistical reasoning and one wonders what other significant differences may have been discounted. Why a subgroup of women underwent both CTG and doppler monitoring certainly needs to be examined more carefully. Fetal outcome was comparable in both groups and yet Almstrom et al advocate a change in antenatal surveillance policy, on the basis of the claim that velocimetry is more simple than cardiotocography, takes a substantially shorter time, and requires less antenatal care resources. I would contest that this form of monitoring needs highly trained staff and advanced (and costly) equipment, which is not at the disposal of every obstetric unit. All units certainly have CTG machines; many general practices also have them so that women need not travel to hospital for monitoring, and if there is an equivocal trace it can be faxed to hospital for further interpretation. Almost 2% of cases had chromosomal abnormalities in which there were anatomical markers detectable by ultrasound scanning. This finding suggests that all suspected cases should be subjected to detailed ultrasound scanning since positive findings may help to guide the subsequent management of the pregnancy and labour.1 Finally, Almstrom’s results suggest that the predictive value of velocimetry is far from perfect. Of course the ideal test will detect impending disaster before it has occurred, and none of the infants with class III measurements showed signs of asphyxia. However, one
We acknowledge the contribution of Bristol-Myers Squibb to the costs of organising the trial.
Endobulln treatment - -I-
MRC HIV Clinical Trials Centre, Department of Clinical Epidemiology,
No Immunoglobulin Infusion
Royal Brompton National Heart and Lung Hospital, London SW3 6NP, UK
JANET H. DARBYSHIRE
JEAN-PIERRE ABOULKER, behalf of the MRC/ANRS International Coordinating Committee for the European/ Australian Alpha Trial
on
Unité de Recherches Statistiques,
INSERM Villejuif, France
1. Khan JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581-87.
A1 B8DR3-associated
expansion in HIV infection SiR.—Dr Oksenhendler and colleagues (July 25, p 207) report 3 HIV-infected white patients characterised by pseudotumoural splenomegaly, polyclonal CD8-positive T-cell expansion, and sharing of the extended A1B8DR3 major histocompatibility complex haplotype. We report a similar case showing that T-cell expansion may not be restricted to lymphoid tissue. A 40-year-old Gambian man was referred to our institution because of acute renal failure (creatinine 1435 pmol/1) in the setting of nephrotic syndrome. He had major splenomegaly and hepatomegaly, peripheral lymphadenopathy, and parotid enlargement. A renal biopsy disclosed focal and segmental glomerulosclerosis and striking interstitial infiltration by numerous CD8-positive, CD25-negative, HLA class II-positive T cells. At the same time, the patient proved HIV-1positive by enzyme-linked immunosorbent assay and western blot. Serological tests for HIV-2, HTLV-1, and HTLV-2 were negative. No opportunistic infection was found. CD4-positive and CD8-positive T-cell counts were 228/ul and 1292/ul, respectively. Salivary gland biopsy showed a lymphocytic infiltrate compatible with a diagnosis of Sjogren’s syndrome. HLA typing was A1B8DR3. Treatment by zidovudine and methylprednisolone resulted in sustained improvement in renal function (creatinine 376 umot/1), and haemodialysis was stopped for 10 months. This report shows that the A1B8DR3-linked CD8-positive T-cell expansion described by Oksenhendler et al in HIV-1infected patients may not arise only in the spleen and that it can involve organs outside the lymphoid system. We suggest that this expansion might account for some visceral complications of HIV infection, such as interstitial nephritis. It may, in some cases, be amenable to antiretroviral and corticosteroid treatment. Service of Clinical Immunology, INSERM U25, and Laboratory of Anatomy and Renal
Pathology,
Hôpital Necker, 75743 Paris, France
Survival of AIDS patients after IVIG therapy.
CD8-positive T-cell
groups of patients were similar in age, weight, low number of CD4 cells, treatment, previous infections, and time between AIDS and entry to the study. All patients had been receiving antiretroviral therapy for 3 months or more at the beginning of study. Clinical evaluation was every month before every IVIG administration.
Laboratory tests (serum immunoglobulins, complement fractions, &bgr;2-microglobulin, transaminases, T-cell counts [CD2, CD3, CD4, or CD8 phenotype], and B-cell counts [CD19, CD20, or CD21 phenotype]) were done every 3 months. IVIG infusions were well tolerated in all patients. No high temperatures, headache, or nausea were observed and no modification of the infusion schedule was necessary in any patient at any time. Survival was significantly better in the IVIG-treated group than in the controls (figure, p < 0-01). 50% of IVIG patients survived 450 days, while less than 50% reached a 200-day survival among controls. After 12 months of follow-up, 9 patients in the IVIG group were alive compared with 3 controls. In addition, and as a possible explanation, the episodes of serious and moderate bacterial or viral infections were fewer in the IVIG-treated group. This study establishes that IVIG has some clinical benefit in adult patients with AIDS. The mechanism of this benefit and the selection of the most appropriate patients deserve further
investigations. Transplantation and Clinical Immunology Unit, Pavillion P, Hôpital Edouard Herriot, 69437 Lyon, France
T. SAINT-MARC J-L. TOURAINE
N. BERRA
1. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency disease. N Engl J Med 1991; 325: 110-17. 2. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 325: 73-80.
JEAN-PAUL VIARD LAURE-HÉLÈNE NOËL DOMINIQUE DROZ JEAN-FRANÇOIS BACH
Beneficial effects of intravenous immunoglobulins in AIDS SiR,—With the introduction of intravenous formulations, the use of immunoglobulins, once limited to IgG replacement in severe humoral immunodeficiencies, has been extended to include the prevention or treatment of infections and immunological disorders.1 Controlled studies in children with HIV infection have shown that immunoglobulin reduces the frequency of bacterial infection and morbidity without changing mortality? We have evaluated the clinical and immunological effects of systematic and regular infusions of immunoglobulins in adults with severe deficiency of cell-mediated immunity and of antibody production because of HIV infection. Between January, 1990, and October, 1991, 24 AIDS patients were enrolled in a prospective trial. All patients were randomised to receive either no additional treatment (controls) or a monthly infusion of intravenous immunoglobulin (IVIG) (Endobulin, lmmunoFrance) at 200 mg/kg for at least 12 months. The two
Role of glucose and insulin resistance in development of type 2 diabetes mellitus SIR,-Dr Martin and colleagues’ study (Oct 17, p 925) of the predictive power of measures of insulin resistance (SD and insulin-independent glucose elimination (Sg) in the development of non-insulin dependent diabetes mellitus (NIDDM) is to be welcomed. This large prospective study of the offspring of parents with NIDDM in 6-25 years of follow-up predicted some 75% of cases of diabetes in subjects with the lowest quintiles of both S; and Sg, who had normal glycaemia at the outset of the study, and for at least 10 years before the onset of NIDDM. By contrast, no offspring in the highest quintile of Sj and Sg developed diabetes in this time. The technique used by Martin et al was the standard intravenous glucose tolerance test (IVGTT) with analysis by the minimum model teclmique.1 A feature of Martin’s study was the use of a higher dose of glucose (05g/kg) than that used by Bergman et aU This will have had the effect of increasing the endogenous insulin response, thus improving the success rate of the subsequent modelling.2 Martin et al successfully analysed 97% of cases. Our experience with this technique has been similar,3-S with an average 96%
success rate.
1348
Minimum modelling of the IVGTT uses a complex analytical technique but the clinical procedure is straightforward and applicable to large groups, unlike the reference standard method for measuring insulin resistance, the euglycaemic clamp. In addition the minimum model provides other important infonnation-for example, the glucose-dependent glucose disappearance rate, Sg, which, according to Martin et al, has almost as good predictive power as measurement of Sj for development of NIDDM. A further refinement of the minimum model technique enables derivation of terms for first and second phase insulin delivery, 01 and 02’ It must be emphasised, however, that these are misleadingly referred to as pancreatic insulin secretion measures by Martin et al. Rather, 0l and 0 refer to insulin delivery into the general circulation, after a large and probably variable proportion of newly secreted insulin has been extracted by the liver.6 Hepatic insulin extraction is reduced in obesity and most of those who developed diabetes in Martin’s study were obese. There may, therefore, have been an impaired pancreatic response to glucose in these subjects, which was disguised by reduced hepatic insulin extraction. The simultaneous measurement of plasma C-peptide (not available when Martin et al’s study was begun) would enable this uncertainty to
be resolved.7
Finally, Martin et al show that predictions of the future development of NIDDM may become possible, especially for vulnerable groups, and in this respect the technique may play a part in diabetes prevention, similar to that of measurement of serum cholesterol and lipoproteins in the prediction of coronary heart disease.
Wynn Institute for Metabolic Research, London NW8 9SQ, UK
IAN F. GODSLAND CHRISTOPHER WALTON VICTOR WYNN
Bergman R, Ider Y, Bowden C, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979; 236: E667-77. 2. Yang Y, Youn J, Bergman R. Modified protocols improve insulin sensitivity estimation using the minimal model. Am J Physiol 1987; 253: E595-602. 3. Bruce R, Godsland I, Stevenson J, et al. Danazol induces resistance to both insulin and glucagon in young women. Chn Sci 1992; 82: 211-17. 4. Walton C, Godsland I, Proudler A, Felton C, Wynn V. Evaluation of four mathematical models of glucose and insulin dynamics with analysis of the effects of age and obesity. Am J Physiol 1992; 262: E755-62. 5. Godsland I, Crook D, Walton C, Wynn V, Oliver M. Influence of insulin resistance, secretion, and clearance on serum cholesterol, triclycerides, lipoprotein cholesterol, and blood pressure in healthy men. Arterioscler Thromb 1992; 12: 1030-35. 6. Horwitz D, Starr J, Mako M, Blackard W, Rubenstein A. Proinsulin, insulin and C-peptide concentrations in human portal and peripheral blood. J Clin Invest 1975; 1.
55: 1278-83. 7. Watanabe R, Vølund A, Roy S, Bergman R. Prehepatic beta-cell secretion during the intravenous glucose tolerance test in humans: application of a combined model of insulin and C-peptide kinetics. J Clin Endocrinol Metab 1989; 69: 790-97.
SIR,-Dr Martin and colleagues report data suggesting defects in insulin sensitivity and non-insulin-mediated glucose disposal as the primary determinants of type 2 (non-insulin dependent) diabetes. Whereas reduced insulin sensitivity has clearly an important role in the pathophysiology of type 2 diabetes, we feel that the data presented do not necessarily prove that it is insulin insensitivity rather than beta-cell dysfunction that is the primary abnormality. Type 2 diabetes is a heterogenous disease and the primary defect varies according to the population studied. Thus, these findings in offspring of diabetic parents may not be generally applicable to all those with type 2 disease. Although insulin insensitivity seems important in certain populations,! in other subsets a genetically determined defect in beta-cell function is the primary defect.2 Even in individuals with reduced insulin sensitivity, beta-cell deficiency is a prerequisite for the development of diabetes. In this respect, it is noteworthy that subjects with some of the distinct syndromes characterised by severe insulin resistance due to inherited disorders of the insulin receptors frequently do not have diabetes, provided that they have adequate beta-cell function.4,5 The methods used in Martin’s study were clearly not designed to detect subtle early defects in insulin secretion but it is notable that in the few subjects studied several times a reduction in beta-cell function preceded the development of diabetes. Furthermore, an increase in the proportion of proinsulin is one of the features of type 2 diabetes.6 The assay for insulin used by investigators would be
expected to cross-react with proinsulin and thus underestimate insulin sensitivity in those individuals with beta-cell dysfunction characterised by increased secretion of proinsulin-like molecules. The measurement of biologically active insulin in these individuals with the new specific insulin assay7 may well reveal evidence of beta-cell deficiencv rather than increased beta-cell function. Department of Medicine, Manchester Royal Infirmary, Manchester M13 9WL, UK
SUDHESH KUMAR ANDREW BOULTON
Doncaster Royal Infirmary, Doncaster
JOHN HOSKER
1. Knowler WC, Pettit DJ, Saad MF, Bennett PH. Diabetes mellitus in the Pima Indians: incidence, risk factors, and pathogenesis. Diabetes Metab Rev 1990; 6: 1-27. 2. Hattersley AT, Turner RC, Permutt MA, et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 1992; 339: 1307-10. 3. Turner RC, Holman RR. Insulin rather than glucose homoeostasis in the pathophysiology of diabetes. Lancet 1976; i: 1272-74. 4. Moller DA, Flier JS Insulin resistance: mechanisms, syndromes, and implications. N Engl J Med 1991; 325: 938-48. 5. Flier JS, Young JB, Landberg L. Familial insulin resistance with acanthosis nigricans, acral hypertrophy, and muscle cramps. N Engl J Med 1984; 303: 970-73. 6. Porte D Jr, Kahn SE. Hyperproinsulinaemia and amyloid in NIDDM. Diabetes 1989; 38: 1333-36. 7. Sobey WJ, Beer SF, Carrington CA, et al. Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65-66 and 32-33 split proinsulins. Biochem J 1989; 260: 535-41.
Cardiotocography and doppler velocimetry for surveillance of small-for-gestational-age
fetuses SIR,-Dr Almstrom and colleagues (Oct 17, p 936) evaluate a technique that shows great promise. However, before their recommendations can be implemented, their study needs closer scrutiny, clarification, and comment. They claim that their two groups are matched in everything apart from smoking, which, as they rightly point out, is associated with poorer outcome. In fact the doppler group has the higher proportion of smokers and yet there were significantly more operative interventions for fetal distress in the cardiotocography (CTG) group. This finding implies either that doppler velocimetry has some therapeutic effect in the prevention of fetal hypoxia and intrapartum fetal distress or, more likely, that the groups were not as new
matched as
is led to believe. Indeed they go on to say that the had doppler group "significantly more operations due to breech presentations and fetopelvic disproportion" whereas the CTG group had significantly more adverse factors such as pre-eclampsia and oligohydramnios. I believe that the groups are not comparable, which might account for the differences in the incidence of fetal distress. Furthermore, to suppose that many of these significant differences were due to chance is contrary to statistical reasoning and one wonders what other significant differences may have been discounted. Why a subgroup of women underwent both CTG and doppler monitoring certainly needs to be examined more carefully. Fetal outcome was comparable in both groups and yet Almstrom et al advocate a change in antenatal surveillance policy, on the basis of the claim that velocimetry is more simple than cardiotocography, takes a substantially shorter time, and requires less antenatal care resources. I would contest that this form of monitoring needs highly trained staff and advanced (and costly) equipment, which is not at the disposal of every obstetric unit. All units certainly have CTG machines; many general practices also have them so that women need not travel to hospital for monitoring, and if there is an equivocal trace it can be faxed to hospital for further interpretation. Almost 2% of cases had chromosomal abnormalities in which there were anatomical markers detectable by ultrasound scanning. This finding suggests that all suspected cases should be subjected to detailed ultrasound scanning since positive findings may help to guide the subsequent management of the pregnancy and labour.1 Finally, Almstrom’s results suggest that the predictive value of velocimetry is far from perfect. Of course the ideal test will detect impending disaster before it has occurred, and none of the infants with class III measurements showed signs of asphyxia. However, one
